1. Field of the Invention
The present invention relates generally to the fields of medicine, immunology, neurology and pathology. More particularly, it concerns the development of immunoreagents for use in treating neuromyelitis optica (NMO).
2. Background of the Invention
AQP4 (aquaporin-4) is a water channel expressed in astrocytes throughout the central nervous system (Lennon et al., 2005) which is involved in water balance in brain (Manley et al., 2000; Papadopoulos et al., 2004) and spinal cord (Saadoun et al., 2008), sensory signal transduction (Li and Verkman, 2001; Lu et al., 2008) and neuroexcitatory phenomena including seizure activity (Binder et al., 2006) and cortical spreading depression (Padmawar et al., 2005) and astrocyte migration and glial scarring (Saadoun et al., 2005; Auguste et al., 2007). AQP4 is expressed in astrocytes as two major isoforms: a long (M1) isoform with translation initiation at Met-1, and a shorter (M23) isoform with translation initiation at Met-23 (Hasegawa et al., 1994; Jung et al., 1994; Yang et al., 1995; Lu et al., 1996). M23 AQP4 assembles in membranes as regular square arrays called orthogonal arrays of particles (OAPs), which were originally seen by freeze-fracture electron microscopy (Landis and Reese, 1974; Wolburg, 1995). OAP formation by M23 results from tetramer-tetramer interactions involving residues just downstream of Met-23 at its cytoplasmic N-terminus, while residues in M1 AQP4 just upstream of Met-23 disrupt this interaction (Crane and Verkman, 2009). While M1 does not form OAPs on its own, it can co-assemble with M23 in heterotetramers that limit OAP size (Neely et al., 1999; Furman et al., 2003; Crane et al. (2009); Tajima et al., 2010). The biological significance of OAP formation by AQP4 remains unknown, with speculated functions including cell-cell adhesion, enhanced AQP4 water permeability, and AQP4 polarization to astrocyte end-feet.
A defining feature of the neuroinflammatory demyelinating disease neuromyelitis optica (NMO) is the presence of serum autoantibodies (NMO-IgG) against AQP4. The presence of NMO-IgG is specific for NMO, and in some reports serum NMO-IgG titers correlate with NMO disease activity (Matiello et al., 2008; Jujus et al., 2008). Studies in rodents suggest that NMO-IgG is pathogenic in NMO. Human NMO-IgG produces many features of NMO disease in rats with pre-existing experimental autoimmune encephalomyelitis (Bennett et al., 2009; Bradl et al., 2009) or pre-treated with complete Freund's adjuvant (Kinoshita et al., 2010), and in naïve mice when injected together with human complement (Saadoun et al., 2010). These animals develop characteristic NMO lesions with neuroinflammation, perivascular deposition of activated complement, demyelination, and loss of astrocyte GFAP and AQP4 immunoreactivity. At present, there remain limited treatments for symptoms of NMO with no known therapies that prevent the underlying inflammatory event.